Recurrent aphthous ulcers (RAU) or oral canker sores are the most common oral lesions afflicting humans. Studies have shown such ulcers affect 18% to 50% of the general population. As the name suggests, RAU lesions tend to recur in susceptible patients, often lasting for weeks. These lesions can be characterized as necrotizing ulcerations of oral mucosal tissue which are located on soft, non-keratinized mucosa. The lesions are painful, affect nutritional intake, and disrupt oral hygiene. They lead commonly to secondary infections by opportunistic organisms and sometimes result in scarring.
The etiology of RAU has been linked to several causative factors including allergies, trauma, stress, autoimmune dysfunction, nutritional deficiencies, microbial infection, hormonal changes, and systemic disease. However, several studies have shown that whatever the specific etiology in a particular patient, the clinical manifestations of RAU are due to an altered immune response. Immunosuppressive steroids such as triamcinolone acetonide are known to be effective in the treatment of RAU. A problem with steroidal therapy for RAU however, is that administration in large doses or over extended periods can cause adrenal suppression and atrophy. The dosage necessary for steroidal therapy to have therapeutic effect for RAU can be lessened, thereby decreasing the opportunity and magnitude of harmful side effects, if the therapy is applied topically rather than systemically. Furthermore, treatment periods necessary to achieve the desired therapeutic effect can be shortened if the form of the product encourages patient compliance in applying the medication on a prescribed schedule.
Attempts at delivery of medication to the oral mucosa have included bioadhesive compositions based primarily on organic cellulose, such as disclosed in Reissue Pat. No. RE 33,093 issued to Schiraldi et al., and polycarbophils disclosed in U.S. Pat. No. 4,615,697 issued to Robinson. The major disadvantages of such compositions is that they are aqueous systems which do not provide as rapid symptomatic relief as the compositions of the present invention, and which are relatively easily removed from the oral mucosa by the flow of saliva.
U.S. Pat. No. 4,948,580 to Browning describes a bioadhesive composition comprising a freeze-dried polymer mixture formed of the copolymer poly(methyl vinyl ether/maleic anhydride) and gelatin dispersed in an ointment base such as mineral oil containing dispersed polyethylene. The freeze-dried combination of polymer and gelatin is reported to be a synergistic combination having enhanced muco-adhesive properties compared to a simple mixture.
U.S. Pat. Nos. 5,112,620 and 5,714,165 to Repka describe combining the therapeutic effect of steroids to counter the dysfunctional immune response associated with RAU, with a local anesthetic to provide immediate symptomatic relief, in an organic base material which provides delivery of the active medications to the lesions. The base material is a bioadhesive composition having wet adherent properties which is not readily displaced from the oral mucosa even in the presence of saliva, and which allows the active medications to remain concentrated and localized over the RAU lesions for an extended treatment period. A formulation prepared in accordance with the Repka patents, containing 0.1% TAA and 2% lidocaine, was able to maintain at least 90% of the initial TAA concentration for 3 months under accelerated storage conditions of 40° C. and 75% relative humidity; however, surprisingly, the formulation was unable to maintain at least 90% of its initial concentration of TAA for more than 13 months under standard storage conditions of 25° C. and 60% relative humidity.
Ideally, a therapeutic composition has an extended shelf life. Due to the realities of production, distribution, and retail sales, product preferably has a shelf life of at least 12 months, preferably at least 18 months, more preferably at least 24 months, and still more preferably at least 36 months. Such a characteristic is particularly advantageous in the treatment of RAU because the ulcers reoccur in susceptible patients. A TAA formulation with a long shelf life would speed healing by allowing susceptible patients to keep the therapeutic formulation on hand so they may apply the formulation at the first appearance of the ulcer(s).
The U.S. Food and Drug Administration measures shelf life as the time (days/months) for which a product retains, within specified limits, the same properties and characteristics that it possessed at the time of its manufacture. [Reference—Guideline for Industry—Stability Testing of New Drug Substances and Products, ICH]. The “specified limits” for Formulation B of Example 1 are: TAA concentration of 90-110% w/w and lidocaine concentration of 95-105% w/w of label claim.
Methods of stabilizing aqueous and alcoholic solutions of TAA are known. TAA has been stabilized in aqueous solutions with an acidic pH. Gupta reports that the optimum pH for TAA stability in aqueous solution was measured to be about 3.4 (Gupta, V. D., “Stability of triamcinolone acetonide solutions as determined by high-performance liquid chromatography,” J. Pharm. Sci., 72:1453-6 (1983)). Ungphaiboon et al. report that decomposition of TAA in aqueous solutions was minimal at pH 3.4 and that above pH 5.5 the rate of TAA decomposition increased rapidly (Ungphaiboon et al., “Formulation and efficacy of triamcinolone acetonide mouthwash for treating oral lichen planus,” Am. J. Health-Syst. Pharm., 62:485-91 (2005)). Ungphaiboon et al. suggest that buffering agents and antioxidants may be added to a TAA formulation to increase its stability. Xu et al. reported that solutions containing lidocaine hydrochloride, chlorhexidine gluconate, and TAA were stable with respect to TAA degradation after storage at room temperature for one year. (Xu et al., “Simultaneous determination of lignocaine hydrochloride, chlorhexidine gluconate, and triamcinolone acetonide in suspension by reversed-phase HPLC,” J. Liq. Chrom. & Re. Technol., 22(13):2071-91 (1999)).
The Repka patents suggest stabilizing a bioadhesive TAA formulation by the addition of antioxidants such as butylated hydroxytoluene and butylated hydroxyanisole. However, it has been discovered that these antioxidants were not effective in adequately prolonging the storage stability of the Repka based formulation. Accordingly, there is a need for such compositions having enhanced storage stability.